(1) Field of the Invention
The invention concerns a procedure according to the generic part of Patent claim 1 and a device according to the generic part of Patent claim 10 for implementing it.
(2) Description of Related Art
Human sugar disease (Diabetes mellitus) is characterized by improper regulation of the metabolism of grape sugar (glucose) in the body and body fluids, with continuous or sporadic elevated concentrations (reflections) of it in the body (hyperglycemia) or, in case of infections, sudden seriously lowered concentrations (hypoglycemia). An excessive blood level causes several pathogenic changes, especially in the blood vessels, some of those lead to extremely serious consequences, such as blindness, loss of kidney function, cardiac infarcts and death of the extremities (gangrene). An inadequate blood level causes, in particular, irreversible death of nerve cells. Therapy of Diabetes mellitus requires that the blood glucose level be maintained consistently at values within a suitable range and, at least in its more severe forms, requires administration of the natural body hormone insulin. The insulin acts to lower the body glucose level. On the other hand, if the sugar level is too low, administration of grape sugar is required. The amount of insulin to be injected, or the need for taking glucose, depends on the concentration of glucosexe2x80x94both the current level and its course during the day. Therefore, the concentration must be measured often to frequently every day, usually by the patient himself. However, it is not as possible to test during sleep. And the biochemical methods for measuring the glucose concentration, now used almost exclusively in medicine, require drawing fresh blood every time, after injuring oneself every time, usually at the fingertip; and they give only instantaneous values. At present there is no method for continuing measurement of the current grape sugar concentrations with sufficient accuracy over the long term. Such a method would be extremely desirable and helpful for the patients.
The following survey of the state of the art is derived from the latest research results, presented at the 33rd Annual Meeting of the German Diabetes Society (Leipzig, May 1998) and from the available patent literature.
Attempts to utilize the biochemical methods mentioned by immobilizing the enzymes used in an implantable probe have as yet been only partially successful. In contact with the body fluids, the enzyme loses its activity, and the sensor must be replaced after no more than a few days. Thus there are no implantable probes under consideration, but only insertable ones, with all the disadvantages of a wound kept open for a long period (the insertion site). Therefore, only detectors based on physical methods of measurement are suitable for implantation, as presumably only those can be stable for an extended period.
Research on developing sensors which measure through the skin (transcutaneously) by optical methods, based on absorption or scattered light photometry or spectrometry, the former particularly by means if infrared radiation, are at present far from being ready for use.
One suitable physical method on the basis of which an implantable glucose sensor could be developed is optical rotation. That is the rotation of the vibration plane of polarized light by optically active substances, of which dissolved glucose is one. It dominates the optical rotation of the body fluids. The magnitude of the rotation depends both on the concentration of the substance and on the path length of the light through the solution. As a result, the concentration of the substance can be determined from the angle of rotation. But if the concentration of the substance being determined is low, as for glucose in the body, it is necessary either to extend the light path suitably to increase the angle of rotation, and/or to increase the sensitivity of the sensor. Both alternatives lead to problems, particularly if the measuring device is to be miniaturized. The object of this invention is a process for determining very small angles of rotation, the characteristics of which are adequate for development of an implantable glucose sensor.
DE 27 24 543 C2 describes a polarimeter for measuring blood glucose. Its principle of operation has a semitransparent mirror which produces two partial beams by reflection and transmission. The difference in the light intensities of the two beams (xe2x80x9creference beamxe2x80x9d and xe2x80x9cmain beamxe2x80x9d) is determined as a measure of the angle of rotation. But that depends on the total intensity of the measuring light. Fluctuations in that are an important factor disturbing the measurement signal.
EP 00 30 610 B1 contains a further development of DE 27 24 543 C2, a polarimeter for determining small angles of rotation (from which a glucose sensor could be developed). The procedure is based on reflection of a polarized light beam at a medium of higher refractive index (such as a plane-parallel plate). Then the intensities of the reflected and refracted partial beams are measured. To attain an additional (partial) analyzer action, the angle of incidence used lies between the limiting angle for total reflection and the polarization angle. Following the beam divider, another polarizing filter is introduced into each of the two partial beams. Thus the remaining signal processing uses portions of the total intensity.
EP 01 23 057 A1 and EP 01 53 313 B1 likewise describe a procedure for polarimetry. An optical grooved grating acts as the beam divider, producing several partial beams. Information about the plane of polarization of the light emerging from the sample is determined from the reduced light intensity of a sample beam after passage through a polarizing filter acting as an analyzer. The quotient of the signals from the intensity detectors in the reference and sample beams is taken, as a relative signal from the sample beam detector signal, to eliminate the distorting effect of varying total light intensity.
A procedure for accurate determination of the plane of vibration of polarized light is known from U.S. Pat. No. 4,467,204. There the light source is only IR light and the reflecting surface for optical amplification is not disclosed. A miniature design is known from U.S. Pat. No. 4,988,199. There, too, the reflecting surface is absent. None of the patents cited, although none are of very recent date, has yet led to a technological development that has become known. The procedures described apparently cannot meet the requirements stated below.
The following requirements are necessary or desirable for an implantable glucose sensor based on a polarimeter:
The sensor should make it possible to determine the vibration plane of polarized light accurately to 0.3 mxc2x0 (mxc2x0: millidegree).
xe2x80x83(The total optical rotation due to glucose at physiological concentration (about 1000 mg/L) at a linear optical path length of about 3 cm, which can be attained in medical technology, is about 10 mxc2x0. Thus an inaccuracy of 0.3 mxc2x0 at this glucose concentration is equivalent to a relative error of 3%.)
The sensor should preferably not contain any movable parts, as mechanical systems are subject to wear, which can cause trouble in operation.
Finally, the sensor signal must not be affected by the optical transparency of the sample, as body fluids can clearly change their absorbance, for instance, in the case of jaundice (icterus). Therefore the procedure must be real polarimetry and not polarization photometry.
A procedure is described in the characterizing part of claim 1, which meets the stated requirements and can be miniaturized in its technical design. It is described in the characterizing part of claim 9 as a device for carrying out the procedure. This millidegree polarimeter can be developed into an implantable glucose sensor.